Leveraging Tumor Suppressor Inactivation for Osteosarcoma Therapy

利用肿瘤抑制因子失活来治疗骨肉瘤

• 批准号: 10669113
• 负责人: BANG H HOANG
• 金额: $ 41.46万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669113
• 关键词: Address; Alanine; Amputation; Animals; Apoptosis; Cell Cycle; Cell Cycle Progression; Cell Line; Cells; Cessation of life; Childhood; Clinical; Combined Modality Therapy; Complex; Cullin Proteins; Cyclin-Dependent Kinase Inhibitor; Cytotoxic Chemotherapy; Data; Defect; Disease; Dose Limiting; Embryo; Emerging Technologies; F Box Domain; F-Box Proteins; Fibroblasts; Future; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Histologic; Implant; Invaded; Knowledge; Life; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of pituitary gland; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Operative Surgical Procedures; Organoids; Osteoblasts; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pituitary Gland; Play; Population; Positioning Attribute; Pre-Clinical Model; Predisposition; Prognosis; Proliferating; Proteins; Quantitative Reverse Transcriptase PCR; Randomized; Relapse; Role; Skp2 Proteins; Survival Rate; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Threonine; Tissues; Translating; Treatment Protocols; Treatment-related toxicity; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; Western Blotting; burden of illness; cell motility; cell type; chemotherapy; clinically relevant; established cell line; immunoregulation; implantation; improved; innovation; insight; mouse model; multicatalytic endopeptidase complex; neoplastic cell; next generation sequencing; novel; novel therapeutics; osteosarcoma; patient derived xenograft model; pre-clinical; prostate carcinogenesis; screening; side effect; stemness; targeted treatment; transcriptome; transcriptomics; translational impact; translational therapeutics; treatment effect; treatment group; tumor; tumor growth; tumor progression; tumorigenesis

PROJECT SUMMARY Osteosarcoma (OS) is the most common malignant bone tumor, found in the pediatric population and often leads to death due to tumor progression and metastasis. Despite intensive, multimodality treatment protocols with cytotoxic chemotherapy and aggressive surgery, 30-40% of patients still succumb to relapsed and metastatic disease. Current treatment options for these patients are extremely limited. More importantly, the clinical outcome for OS patients has not improved at all during the last four decades. Our long-range goals are to reduce OS disease burden and improve long-term survival by developing molecular-based therapies that target mechanisms of tumor growth and metastasis. The F-box protein s-phase kinase-associated protein-2 (Skp2) is the substrate recognition component of the Skp1-Cullin1-F-box (SCF) complex and considered a key oncogene through its ability to target cell cycle regulators for ubiquitin degradation, regulates cell migration and metastasis. Skp2 interacts with the accessory protein Cks1 to ubiquitinate p27 for degradation, thus promoting cell cycle progression and cancer growth. Currently, the oncogenic mechanisms and therapeutic potential of Skp2 in OS is largely unknown. There are specific and rational reasons for targeting the SCF-Skp2 axis in OS, based upon preliminary data generated by the PI and his colleagues: (1) A high Skp2 expression in OS tissues portends a poor prognosis in patients; (2) High levels of Skp2 are observed in many OS cell types, including established cell lines, patient-derived xenografts, and primary cultures from OS patients; (3) Skp2 deletion effectively blocks pituitary and prostate tumorigenesis in Rb1/p53-deficient mouse models. In OS, genomic sequencing studies reveal a high rate of Rb1/p53 co-inactivation, suggesting that OS may be susceptible to Skp2 blockade; (4) Genetic and drug-induced depletion of Skp2 reduces the proliferation and invasion of OS cell lines and; (5) Mouse embryonic fibroblasts (MEF) and OS tumor cells with Rb1/p53 deletion are more sensitive to SCF-Skp2 inhibition than wild-type and Skp2-deleted cells. Taken together, these data suggest that the SCF-Skp2 complex may offer a unique therapeutic opportunity for treating a tremendously challenging cancer such as OS. We hypothesize that blockade of the SCF-Skp2 complex in the context of Rb1/p53 inactivation will reduce OS progression. This hypothesis will be addressed by the following specific aims: Specific Aim 1 (Oncogenic Mechanisms): To define the pro-oncogenic mechanisms of SCF-Skp2 in Rb1/p53-inactivated OS. Specific Aim 2 (Translational Therapeutics): To determine the effect of inhibiting SCF-Skp2 in preclinical models of Rb1/p53- inactivated OS. Finally, since cancer organoids represent an emerging technology that faithfully replicates the tumor's genetic landscape, we will examine the effect of inhibiting SCF- Skp2 in mouse OS organoids as a proof-of-concept to translate findings into patient-specific therapeutics in the future. The successful completion of this study will be translatable to target the SCF-Skp2 complex to block osteosarcoma progression.

项目总结 骨肉瘤(OS)是最常见的恶性骨肿瘤，见于儿童 而且常常由于肿瘤的进展和转移而导致死亡。尽管 使用细胞毒性化疗和侵袭性的强化、多模式治疗方案 手术后，仍有30-40%的患者死于复发和转移性疾病。当前 这些患者的治疗选择极其有限。更重要的是，临床 在过去的40年里，OS患者的结果根本没有改善。我们的远程 目标是减少OS疾病的负担，并通过开发 以肿瘤生长和转移机制为靶点的分子治疗。F-box 蛋白S相蛋白相关蛋白-2(Skp2)是底物识别成分 Skp1-Cullin1-F-box(SCF)复合体，被认为是一个关键的癌基因，因为它能够 泛素降解的靶细胞周期调节因子，调节细胞迁移和转移。 Skp2与辅助蛋白Cks1相互作用，泛素化p27进行降解，从而 促进细胞周期进展和癌症生长。目前，肿瘤发生机制的研究进展 而Skp2在OS中的治疗潜力在很大程度上是未知的。有具体的和合理的 在操作系统中瞄准SCF-Skp2轴的原因，基于 PI和他的同事：(1)OS组织中Skp2的高表达预示着卵巢癌预后不良 患者；(2)在许多OS细胞类型中观察到高水平的Skp2，包括已建立的细胞 来自OS患者的细胞系、患者来源的异种移植物和原代培养；(3)Skp2缺失 有效阻止Rb1/P53缺陷小鼠模型的垂体和前列腺癌的发生。在……里面 基因组测序研究显示Rb1/P53共失活的比率很高，这表明 OS可能对Skp2的阻断敏感；(4)遗传和药物导致的Skp2的耗竭 减少OS细胞系的增殖和侵袭；(5)小鼠胚胎成纤维细胞 Rb1/P53缺失的MEF和OS肿瘤细胞对SCF-Skp2抑制更敏感 而不是野生型和Skp2缺失的细胞。综上所述，这些数据表明SCF-Skp2 复合体可能提供一个独特的治疗机会来治疗极具挑战性的 癌症，如OS。我们假设在以下背景下对SCF-Skp2复合体的封锁 Rb1/P53失活会减缓OS进展。这一假设将由 以下具体目标：具体目标1(致癌机制)：界定致癌因素 SCF-Skp2在Rb1/P53失活OS中的作用机制特定目标2(翻译 治疗学)：确定抑制SCF-Skp2在Rb1/P53临床前模型中的作用 停用的操作系统。最后，由于癌症有机化合物代表了一种新兴的技术， 忠实地复制了肿瘤的遗传图景，我们将检测抑制SCF- 小鼠OS类器官中的Skp2作为将发现转化为患者特有的概念验证 未来的治疗学。这项研究的成功完成将可转化为目标 SCF-Skp2复合体阻止骨肉瘤进展。